Chalcone derivatives from licorice inhibit human and rat gonadal 3β-hydroxysteroid dehydrogenases as therapeutic uses

In traditional Chinese medicine, licorice (the roots of Glycyrrhiza glabra and G. inflata) has been used to treat inflammation and sexual debility for over 1000 years. Pharmacological studies have identified many biologically active chalcone derivatives from licorice.Human 3β-Hydroxysteroid dehydrogenase 2 (h3β-HSD2) catalyzes the formation of precursors for sex hormones and corticosteroids, which play critical roles in reproduction and metabolism. We explored inhibition and mode action of chalcones of inhibiting h3β-HSD2 and compared it with rat 3β-HSD1.We investigated the inhibition of 5 chalcones on h3β-HSD2 and compared species-dependent difference with 3β-HSD1.The inhibitory strength on h3β-HSD2 was isoliquiritigenin (IC50, 0.391 μM) > licochalcone A (0.494 μM) > licochalcone B (1.485 μM) > echinatin (1.746 μM) >chalcone (100.3 μM). The inhibitory strength on r3β-HSD1 was isoliquiritigenin (IC50, 0.829 μM) > licochalcone A (1.165 μM) > licochalcone B (1.866 μM) > echinatin (2.593 μM) > chalcone (101.2 μM). Docking showed that all chemicals bind steroid and/or NAD+-binding site with the mixed mode. Structure-activity relationship analysis showed that strength was correlated with chemical's hydrogen bond acceptor.Some chalcones are potent h3β-HSD2 and r3β-HSD1 inhibitors, possibly being potential drugs to treat Cushing's syndrome or polycystic ovarian syndrome.